{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T04:59:59Z","timestamp":1785301199563,"version":"3.55.0"},"reference-count":34,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"vor","delay-in-days":27,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82130122"],"award-info":[{"award-number":["82130122"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Chronic pain management remains a major clinical challenge due to the limited availability of effective therapies that avoid severe side effects. The rostral ventromedial medulla (RVM) is a critical brainstem center for pain modulation; however, the neurochemical identity and functional roles of its neuronal subpopulations remain incompletely understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed a series of tests by constructing a complete Freund's adjuvant (CFA)\u2010induced inflammatory nociceptive model and a chronic constrictive injury (CCI) neuropathic pain model combined with behavioral experiments, in\u00a0situ hybridization, chemogenetics, optogenetics, and in\u00a0vivo electrophysiological techniques.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      This study identifies enkephalinergic neurons in the RVM and their projections to the subnucleus reticularis dorsalis (SRD) as a distinct descending pain\u2010inhibitory circuit. RNAscope shows elevated ENK\n                      <jats:sup>RVM<\/jats:sup>\n                      neuron activity in mouse models of inflammatory and neuropathic pain. Bidirectional chemogenetic and optogenetic manipulations demonstrate that inhibiting ENK\n                      <jats:sup>RVM<\/jats:sup>\n                      neurons or their SRD projections induces hyperalgesia, while activation elevates baseline pain thresholds and reverses hyperalgesia in CFA and CCI models. This pathway modulates nociception selectively without affecting anxiety or motor function.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      These findings identify the ENK\n                      <jats:sup>RVM\u2192SRD<\/jats:sup>\n                      pathway as a bidirectional descending circuit for pain inhibition, highlighting its potential as a therapeutic target for analgesic intervention.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cns.71064","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T14:56:27Z","timestamp":1785250587000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The\n                    <scp>\n                      ENK\n                      <sup>RVM<\/sup>\n                    <\/scp>\n                    <sup>\n                      \u2192\n                      <scp>SRD<\/scp>\n                    <\/sup>\n                    Projection Constitutes a Functionally Specific Circuit for Bidirectional Pain Modulation"],"prefix":"10.1002","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8423-0633","authenticated-orcid":false,"given":"Kexing","family":"Wan","sequence":"first","affiliation":[{"name":"Hwamei College of Life and Health Sciences Zhejiang Wanli University  Ningbo Zhejiang China"},{"name":"School of Basic Medicine, Tongji Medical College, Key Laboratory of Neurological Diseases of Hubei Province and National Education Ministry Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajia","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Basic Medicine, Tongji Medical College, Key Laboratory of Neurological Diseases of Hubei Province 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